Levacetylleucine

Levacetylleucine

WeightAverage: 173.212
Monoisotopic: 173.105193347

Chemical FormulaC₈H₁₅NO₃

• N-Acetyl-L-leucine
• CAS 1188-21-2
• acetyl-L-leucine
• Ac-Leu-OH
• N-Acetylleucine
• NSC 206316
• UNII-E915HL7K2O
• 
  NSC-206316

(2S)-2-acetamido-4-methylpentanoic acid

FDA APPROVED 9/24/2024, To treat Niemann-Pick disease type C
Press Release
Drug Trials Snapshot

• Originator University of Munich; University of Oxford
• Developer IntraBio
• Class Acetamides; Amino acids; Esters; Neuroprotectants; Pentanoic acids; Small molecules; Vestibular disorder therapies
• Mechanism of Action Calcium channel modulators

• Orphan Drug StatusYes – Tay-Sachs disease; Niemann-Pick disease type C; Ataxia telangiectasia

Registered Niemann-Pick disease type C

• Phase IIIAtaxia telangiectasia
• Phase IISandhoff disease; Tay-Sachs disease

18 Mar 2025Phase-III clinical trials in Ataxia telangiectasia (In adolescents, In children, In the elderly, In adults) in Switzerland, Slovakia, Spain, Germany, USA, United Kingdom (PO) (NCT06673056)

• 04 Nov 2024IntraBio plans a phase III trial for Ataxia telangiectasia (In children, In adolescents, In adults, In elderly) in the US, Germany, Slovakia, Spain and Switzerland (PO, Suspension) in March 2025 (NCT06673056)
• 24 Sep 2024Registered for Niemann-Pick disease type C (In adolescents, In children, In adults) in USA (PO)

Levacetylleucine (N-acetyl-L-leucine), sold under the brand name Aqneursa, is a medication used for the treatment of neurological manifestations of Niemann-Pick disease type C.^[1][2] Levacetylleucine is a modified version of the amino acid leucine.^[1] It is the L-form of acetylleucine. It is taken by mouth.^[1]

The most common side effects include abdominal pain, difficulty swallowing, upper respiratory tract infections, and vomiting.^[1][2]

Levacetylleucine was approved for medical use in the United States in September 2024.^[1][2][3] Levacetylleucine is the second medication approved by the US Food and Drug Administration (FDA) for the treatment of Niemann-Pick disease type C.^[2] The FDA considers it to be a first-in-class medication.^[4]

DATA

N-acetyl-D, L-leucine is the active ingredient of Tanganil ^® which helps treat vertigo attacks.

 N-Acetyl-D, L-leucine

 Unlike the majority of chemical syntheses of active principles where it is desirable to separate the enanti omers and / or to retain the selective stereo information during the synthesis steps, the synthesis of N-acetyl-D, L-leucine is carried out from L-leucine and therefore involves a racemization step. This racemization takes place before the acetylation step, via a Schiff base formed in situ with salicylic aldehyde (Yamada et al., J. Org. Chem., 1983 48, 843- 846).

Two competitive reactions are then involved: the acetylation of leucine, the main reaction, where acetic anhydride reacts with the amine function of leucinate of sodium to give N-acetyleucinate and the hydrolysis of acetic anhydride to acetic acid, a side reaction described below.

 This synthesis has a molar yield of 70%. The limiting steps are essentially the secondary reaction of hydrolysis of acetic anhydride and the step of isolation of the racemized leucine before the acetylation reaction. Indeed, on an industrial scale, the quantities of products brought into play for isolations prove to be very restrictive.

 There is therefore a real need to develop a new process for the preparation of N-actéyl-D, L-leucine which is faster and more economical.

The inventors thus discovered that the racemization step could be carried out after the L-leucine acetylation step making it possible to avoid a step of isolating the intermediate product and that this process could be carried out in continuous flow. Du Vigneaud & Meyer (J. Biol Chem, 1932, 98, 295-308) had already shown that it was possible to racemize different acetylated amino acids by bringing them into the presence of acetic anhydride for several hours. However, no examples had been made with acetyl leucine. By attempting to reproduce this process with acetyl-leucine, the inventors have thus found that this racemization reaction did not give satisfactory results with acetyl-leucine because of a competitive hydrolysis reaction of acetic anhydride. used. The inventors have also surprisingly discovered that the racemization reaction of N-acetyl-L-leucine could be improved by producing it in a continuous flow. It seems indeed that the realization of this continuous flow process allows better control of the mixing of the reagents and therefore to better control the reaction. The inventors have also shown that the racemization of N-acetyl-L-Leucine in continuous flow was obtained in a very short time of the order of a few minutes.

Furthermore, there is also a need to develop a new method of acetylation of leucine for the preparation of N-actyle-leucine which is faster and more economical. The inventors have discovered that the acetylation reaction of leucine can be improved by making it in a continuous flow. The process according to the invention gives good yields, in a very short time and using fewer reagents compared to the method known hitherto.

 Indeed, DeWitt et al. (J Am Chem Soc (1951) 73 (7) 3359-60) described the preparation of N-acetyl-L-Leucine by reacting L-Leucine with 3 molar equivalents of acetic anhydride and sodium hydroxide for 2 hours 20 minutes. . N-acetyl-L-leucine is then obtained in a yield of only 70-80%. In addition, the authors of this publication clearly indicated that a molar ratio between L-Leucine and acetic anhydride below 2 resulted in much lower yields.

SYNTHESIS

H. D. DeWitt and A. W. Ingersoll. The Preparation of Pure N-Acetyl-L-leucine and L-Leucine. Journal of the American Chemical Society 1951 73 (7), 3359-3360. DOI: 10.1021/ja01151a108

PATENT

https://patents.google.com/patent/WO2012038515A1/en

 EXAMPLES

A. Acetylation of L-Leucine in Continuous Flow

A. L. Study of the molar ratio of acetic anhydride to leucine

 The objective of this study is to define the necessary molar ratio of acetic anhydride so that the acetylation reaction with acetic anhydride is complete and is not disadvantageous by competition with the acetic anhydride hydrolysis reaction. In this study, the residence time in the reactor / exchanger (1 process plate) was set at 9 seconds, for a temperature of the reaction medium of between 25 and 30 ° C.

 The ratio range studied is between 0.9 and 2.0 molar equivalents. The optimum is obtained for a ratio between 1.20 and 2.00, more particularly between 1.30 and 1.60. Below this ratio, the acetylation reaction is disadvantageous compared to the acetic hydrolysis reaction. Beyond this, the drop in pH (acid instead of base) also disadvantages the acetylation reaction.

EXAMPLES 1-10:

A solution of sodium L-leucinate, for passage in continuous flow reactor, is prepared in the following manner: 700 g of L-leucine are dissolved in a solution of 576 g of sodium hydroxide and 3.5 liters of Demineralized Water. This solution is the main fluid process. The reaction between this solution and the acetic anhydride is carried out in a continuous flow in a Boostec® reactor, made of silicon carbide. The reactor / exchanger is configured with an injection-type process plate comprised between two utility plates. The volume of the process plate is 10 mL. The temperature in the reactor is maintained by the circulation of a coolant heated by a thermostatic bath. The transformation of L-leucine to N-acetyl-L-leucine is monitored online by quantitative Raman spectroscopy. This method of analysis is calibrated beforehand with solutions of known concentration prepared with pure L-leucine and N-acetyl-L-leucine.

Example 1

The temperature of the thermostated bath is set at 25 ° C. The sodium leucinate solution and pure acetic anhydride are introduced into the reactor at respective flow rates set at 4.06 kg.h ^-1 and 0.42 kg h ^-1 . These flow rates correspond to a molar ratio of acetic anhydride to leucine of 0.91 equivalents. The total flow rate is therefore 4.48 kg.h ^-1 , which corresponds to a residence time (equivalent to the reaction time) of 8.7 s The yield of acetyl-L-leucinate determined by Raman spectroscopy online at the outlet of the reactor is 40% Example 2:

The temperature of the thermostated bath is set at 25 ° C. The sodium leucinate solution and pure acetic anhydride are introduced into the reactor at respective flow rates set at 3.95 kg · h ^-1 and 0.45 kg · h ^-1 . These flow rates correspond to a molar ratio of acetic anhydride to leucine of 1.01 equivalents. The total flow rate is therefore 4.40 kg.h ^-1 , which corresponds to a residence time of 8.9 S. The yield of acetyl-L-leucinate determined by in-line Raman spectroscopy at the outlet of the reactor is 52.degree. %.

Example 3

The temperature of the thermostated bath is set at 25 ° C. The sodium leucinate solution and pure acetic anhydride are introduced into the reactor at respective flow rates set at 3.89 kg · h ^-1 and 0.52 kg · h ^-1 . These flow rates correspond to a molar ratio of acetic anhydride to leucine of 1.18 equivalents. The total flow rate is therefore 4.41 kg.h ^-1 , which corresponds to a residence time of 8.9 S. The yield of acetyl-L-leucinate determined by in-line Raman spectroscopy at the outlet of the reactor is 57.degree. %. Example 4

The temperature of the thermostated bath is set at 25 ° C. The sodium leucinate solution and pure acetic anhydride are introduced into the reactor at respective flow rates set at 3.82 kg. h ^-1 and 0.57 kg h ^-1 . These flow rates correspond to a molar ratio of acetic anhydride to leucine of 1.32 equivalents. The total flow is therefore 4.39 kg. h ^“1 , which corresponds to a residence time of 8.9 S. The yield of acetyl-L-leucinate determined by in-line Raman spectroscopy at the outlet of the reactor is 83%.

Example 5

The temperature of the thermostated bath is set at 25 ° C. The sodium leucinate solution and pure acetic anhydride are introduced into the reactor at respective rates set at 3.64 kg. h ^-1 and 0.55 kg h ^-1 . These flow rates correspond to a molar ratio of acetic anhydride to leucine of 1.34 equivalents. The total flow is therefore 4, 19 kg. h ^“1 , which corresponds to a residence time of 9.4 s The yield of acetyl-L-leucinate determined by in-line Raman spectroscopy at the outlet of the reactor is 98%.

Example 6

The temperature of the thermostated bath is set at 25 ° C. The sodium leucinate solution and pure acetic anhydride are introduced into the reactor at respective rates set at 3.66 kg. h ¹ and 0.62 kg h ^-1 . These flow rates correspond to a molar ratio of acetic anhydride to leucine of 1.50 equivalents. The total flow is therefore 4.28 kg. h ^“1 , which corresponds to a residence time of 9.2 s The yield of acetyl-L-leucinate determined by in-line Raman spectroscopy at the outlet of the reactor is 96%.

The temperature of the thermostated bath is set at 25 ° C. The sodium leucinate solution and pure acetic anhydride are introduced into the reactor at respective flow rates fixed at 3.67 kg. h ^-1 and 0.64 kg h ^-1 . These flow rates correspond to a molar ratio of acetic anhydride to leucine of 1.54 equivalents. The total flow is therefore 4.31 kg. h ^“1 , which corresponds to a residence time of 9.1 sec The yield of acetyl-L-leucinate determined by in-line Raman spectroscopy at the outlet of the reactor is 100%. Example 8

The temperature of the thermostated bath is set at 25 ° C. The sodium leucinate solution and pure acetic anhydride are introduced into the reactor at respective flow rates set at 3.63 kg. h ^-1 and 0.73 kg h ^-1 . These flow rates correspond to a molar ratio of acetic anhydride to leucine of 1.78 equivalents. The total flow is therefore 4.36 kg. h ^“1 , which corresponds to a residence time of 9.0 s The yield of acetyl-L-leucinate determined by in-line Raman spectroscopy at the outlet of the reactor is 90%.

PATENT

https://patents.google.com/patent/CN104592052A/en

Example 1:

100gL-leucine adds 1000ML2NNaOH rising temperature for dissolving, adds 1ML salicylic aldehyde, 95 degree of insulations of intensification 3 hours, recording optically-active is 0, be cooled to 5 degree and keep, dripping 80ML diacetyl oxide, dropwise maintenance 0.5 hour, be warmed up to 60 degree, add proper amount of active carbon decolouring, add 160ML HCl and adjust PH 2.5, be cooled to 4 degree, suction filtration, the 118g. of oven dry

Example 2:

100gL-leucine adds 1200ML 2NNaOH rising temperature for dissolving, adds 3ML salicylic aldehyde, 95 degree of insulations of intensification 3 hours, recording optically-active is 0, be cooled to 5 degree and keep, dripping 80ML diacetyl oxide, dropwise maintenance 0.5 hour, be warmed up to 60 degree, add proper amount of active carbon decolouring, add the 3.0. that 180ML HCl adjusts PH, be cooled to 4 degree, suction filtration, the 110g. of oven dry

Example 3:

100gL-leucine adds 1000ML 2NNaOH rising temperature for dissolving, adds 2ML salicylic aldehyde, 95 degree of insulations of intensification 3 hours, recording optically-active is 0, be cooled to 5 degree and keep, dripping 80ML diacetyl oxide, dropwise maintenance 0.5 hour, be warmed up to 60 degree, add proper amount of active carbon decolouring, add 180ML HCl and adjust PH 3.0, be cooled to 4 degree, suction filtration, the 120g. of oven dry

Medical uses

Levacetylleucine is indicated for the treatment of neurological manifestations of Niemann-Pick disease type C in people weighing at least 15 kilograms (33 lb).^[1][2]

Adverse effects

The most common side effects include abdominal pain, difficulty swallowing, upper respiratory tract infections, and vomiting.^[2]

Levacetylleucine may cause embryo-fetal harm if used during pregnancy.^[1][2]

History

The safety and efficacy of levacetylleucine for the treatment of Niemann-Pick disease type C were evaluated in a randomized, double-blind, placebo-controlled, two-period, 24-week crossover study.^[2] The duration was twelve weeks for each treatment period.^[2] The study enrolled 60 participants.^[2] To be eligible for the study participants had to be four years of age or older with a confirmed diagnosis of Niemann-Pick disease type C and at least mild disease-related neurological symptoms.^[2] Participants could receive miglustat, an enzyme inhibitor, as background treatment in the study.^[2]

The US Food and Drug Administration (FDA) granted the application for levacetylleucine priority review, fast track, orphan drug, and rare pediatric disease designations.^[2] The FDA granted approval of Aqneursa to IntraBio Inc.^[2]

Society and culture

Legal status

Levacetylleucine was approved for medical use in the United States in September 2024.^[1][2][5]

Names

Levacetylleucine is the international nonproprietary name.^[6]

Research

Levacetylleucine is being studied for the treatment of GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases),^[7] ataxia-telangiectasia,^[8] Lewy body dementia,^[9] amyotrophic lateral sclerosis, restless legs syndrome, multiple sclerosis, and migraine.^[10]

References

1. ^ Jump up to:^{a b c d e f g h i} “Aqneursa- levacetylleucine granule, for suspension”. DailyMed. 24 September 2024. Retrieved 5 October 2024.
2. ^ Jump up to:^{a b c d e f g h i j k l m n o} “FDA Approves New Drug to Treat Niemann-Pick Disease, Type C”. U.S. Food and Drug Administration (Press release). 24 September 2024. Retrieved 25 September 2024.  This article incorporates text from this source, which is in the public domain.
3. ^ “IntraBio Announces U.S. FDA Approval of Aqneursa for the Treatment of Niemann-Pick Disease Type C”. IntraBio (Press release). 25 September 2024. Retrieved 26 September 2024.
4. ^ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
5. ^ “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 29 November 2024.
6. ^ World Health Organization (2024). “International nonproprietary names for pharmaceutical substances (INN): proposed INN: list 131”. WHO Drug Information. 38 (2). hdl:10665/378367. ISBN 9789240098558.
7. ^ Martakis K, Claassen J, Gascon-Bayari J, Goldschagg N, Hahn A, Hassan A, et al. (March 2023). “Efficacy and Safety of N-Acetyl-l-Leucine in Children and Adults With GM2 Gangliosidoses”. Neurology. 100 (10): e1072 – e1083. doi:10.1212/WNL.0000000000201660. PMC 9990862. PMID 36456200.
8. ^ Fields T, Patterson M, Bremova-Ertl T, Belcher G, Billington I, Churchill GC, et al. (January 2021). “A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia”. Trials. 22 (1): 84. doi:10.1186/s13063-020-05009-3. PMC 7821839. PMID 33482890.
9. ^ Passmore P (15 April 2014). A clinical trial to test amlodipine as a new treatment for vascular dementia. ISRCTN registry (Report). doi:10.1186/isrctn31208535.
10. ^ Strupp M, Bayer O, Feil K, Straube A (February 2019). “Prophylactic treatment of migraine with and without aura with acetyl-DL-leucine: a case series”. Journal of Neurology. 266 (2): 525–529. doi:10.1007/s00415-018-9155-6. PMID 30547273. S2CID 56148131.

Further reading

• Churchill GC, Strupp M, Factor C, Bremova-Ertl T, Factor M, Patterson MC, et al. (August 2021). “Acetylation turns leucine into a drug by membrane transporter switching”. Scientific Reports. 11 (1): 15812. Bibcode:2021NatSR..1115812C. doi:10.1038/s41598-021-95255-5. PMC 8338929. PMID 34349180.
• Bremova-Ertl T, Ramaswami U, Brands M, Foltan T, Gautschi M, Gissen P, et al. (February 2024). “Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C”. The New England Journal of Medicine. 390 (5): 421–431. doi:10.1056/NEJMoa2310151. PMID 38294974.
• Tifft CJ (February 2024). “N-Acetyl-l-Leucine and Neurodegenerative Disease”. The New England Journal of Medicine. 390 (5): 467–470. doi:10.1056/NEJMe2313791. PMID 38294981.

External links

• Clinical trial number NCT05163288 for “A Pivotal Study of N-Acetyl-L-Leucine on Niemann-Pick Disease Type C” at ClinicalTrials.gov
• Bremova-Ertl T, Ramaswami U, Brands M, Foltan T, Gautschi M, Gissen P, Gowing F, Hahn A, Jones S, Kay R, Kolnikova M, Arash-Kaps L, Marquardt T, Mengel E, Park JH, Reichmannova S, Schneider SA, Sivananthan S, Walterfang M, Wibawa P, Strupp M, Martakis K: Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C. N Engl J Med. 2024 Feb 1;390(5):421-431. doi: 10.1056/NEJMoa2310151. [Article]
• Fields T, M Bremova T, Billington I, Churchill GC, Evans W, Fields C, Galione A, Kay R, Mathieson T, Martakis K, Patterson M, Platt F, Factor M, Strupp M: N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study. Trials. 2023 May 29;24(1):361. doi: 10.1186/s13063-023-07399-6. [Article]
• FDA Approved Drug Products: Aqneursa (levacetylleucine) for oral suspension (September 2024) [Link]
• FDA News Release: FDA Approves New Drug to Treat Niemann-Pick Disease, Type C [Link]

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